The flavonoids also inhibited in vitro formation of TTR small oligomeric species and in cell culture inhibited pathways involving caspase-3 activation and ER stress that are induced by TTR oligomers. tested. Conclusions Our results highlight the presence of gallate ester moiety as key structural feature of BR351 flavonoids in chemical chaperoning of TTR aggregation. Upon binding to the native tetramer, gallated flavonoids redirect the TTR amyloidogenic pathway into unstructured nontoxic aggregation assemblies more efficiently than their non-gallated forms. General significance Our findings suggest that galloyl moieties greatly enhance flavonoid anti-amyloid chaperone activity and this should be taken into consideration in therapeutic candidate drug discovery. results described above we examined the effect of flavonoids on TTR irregular misfolding and toxicity inside a cell tradition system. Assessment of the effects of different flavonoids on inhibition of TTR aggregation and toxicity appears to correlate closely with i) the presence of gallate ester moiety in the catechin structure and ii) the number of hydroxyl organizations in the B-ring catechin structure. Thus, the overall anti-amyloidogenic activity of flavonoids was: EGCG gallic acid catechin gallate=epicatechin gallate=theaflavin monogallate=theaflavin digallate=tannic acid theaflavin=catechin=epicatechin. Taken together, these results BR351 highlight the importance of the galloyl moiety on TTR anti-amyloidogenic activity associated with tea flavonoids. In support of this hypothesis, we observed a impressive inhibition of TTR amyloidogenicity by gallic acid. This key finding is in agreement with previously reported data concerning the protective effects of flavonoid galloyl esters (i.e gallic acid, epicatechin gallate, EGCG) against -amyloid induced toxicity using main cultures of rat hippocampal cells while magic size . Furthermore, the galloyl moiety seems to be required for major biological and pharmacological activities of tea flavonols, namely free radical-scavenging capabilities  and antiproliferative activity of malignancy cells , . Stochastic conformational analysis performed by Kuzuhara and colleagues exposed many conformations of EGCG and epicatechin gallate indicating that the mobility and flexibility of the galloyl moiety allow these compounds to take on BR351 multiple conformations that may be relevant for connection with different molecular focuses on . In addition, the presence of 3-trihydroxyl organizations attached to the B-ring in EGCG enhances its anti-aggregation effectiveness in comparison to those with dihydroxyl organizations (catechin gallate and epicatechin gallate). Therefore, the number of hydroxyl organizations within the B-ring and D-Ring seems to impact on the anti-amyloidogenic potency of catechin gallate esters. Although we present here the first direct evidence showing the structural-activity associations of tea flavonoids on inhibition of TTR BR351 aggregation, it is most likely BR351 that multimodal activities of tea polyphenols, with emphasis on their neurorescue/neuroregenerative and mitochondrial stabilization actions, may potentiate their protecting effects MCM7 . Pharmacokinetics and bioavailability of tea polyphenols in humans and rodents is definitely poorly defined . However it is known that gut absorption and rate of metabolism of flavonoids varies depending on their chemical difficulty. For instance, monomeric flavan-3-ols are principally soaked up in the small intestine while higher-molecular-weight polymers require prior rate of metabolism into phenolic acids from the action of resident colonic microflora before absorption. Following absorption and moving through the circulatory system, metabolites are excreted in urine in amounts equivalent to about 40% of total flavonoid intake . Taken this into account, different strategies aiming flavonoid bioavailability optimization have been proposed , including EGCG encapsulation in chitosan particles  or the design and semisynthesis O-acyl derivatives of EGCG  or co-treatment with piperine . Neverthless, persuasive evidence from epidemiologic observations and experimental studies in mouse models possess indicated that green tea components (GTE) or EGCG usage have beneficial effects in reducing the risk of neurodegeneration and dementia , , . We have demonstrated previously  that sub-chronic supplementation of FAP mice model with EGCG (100?mg/Kg/day time) decreased TTR deposition along the gastrointestinal tract and peripheral nervous system (PNS). These results have recently been corroborated by an observational statement on the effects of GTE usage in individuals with TTR cardiomyopathy showing an inhibitory effect of green tea and/or GTE within the progression of cardiac amyloidosis . In conclusion, the current work provides strong support for the hypotheses that tea polyphenols, in particular galloyl esters, can act as chemical chaperones that inhibit or redirect normally aggregation-prone amyloidogenic intermediaries onto less dangerous varieties . On basis of the structure-activity studies presented here, we determine the galloyl moiety as the key crucial structure feature for TTR chaperoning by flavonoids. Our findings provide new evidence for comprehensive understanding of the mechanism of TTR toxicity inhibition by polyphenols and may open perspectives for the design and development of innovative disease-modifying medicines for the prevention.